Vasopressin-2 receptor agonists

ABSTRACT

Vasopressin-2 receptor agonists, pharmaceutical compositions thereof and methods for using the foregoing for treating diabetes insipidus, primary nocturnal enuresis, and nocturia.

RELATED APPLICATIONS

This application is a continuation application of U.S. application Ser.No. 14/647,357, filed May 26, 2015, which is a U.S. National Phaseapplication under 35 U.S.C. § 371 of International Patent ApplicationNo. PCT/US2014/048317, filed Jul. 25, 2014, which claims the benefit ofU.S. Provisional Applications 61/859,024 filed Jul. 26, 2013, and61/952,073 filed Mar. 12, 2014, all of which are hereby incorporated byreference in their entirety.

SEQUENCE LISTING

This instant application contains a Sequence Listing which has beensubmitted electronically in ASCII format and is hereby incorporated byreference in its entirety. Said ASCII copy, created on Mar. 2, 2016, isnamed 27521-0082US1_SL.txt and is 713 bytes in size.

FIELD

The present invention relates to novel compounds with agonist activityat the vasopressin-2 (V₂) receptor, pharmaceutical compositionscomprising these, and use of the compounds for the manufacture ofmedicaments for treatment of diseases.

BACKGROUND

There are three known subtypes of vasopressin receptors, V_(1a), V_(1b)and V₂. The V_(1b) receptor is also known as the V₃ receptor and theV_(1a) receptor is also known as the V₁ receptor. Each subtype has adistinct pattern of expression in tissues, with V₂ found primarily inthe kidney, where it mediates the antidiuretic activity of theendogenous ligand vasopressin (Favory et al, 2009). V_(1b) is widelydistributed in the brain (Hernando et al., 2001). V_(1a) is found in avariety of tissues, including smooth muscle, liver, kidney, platelets,spleen and brain (Zingg, 1996; Ostrowski et al., 1994).

Agonists of the V₂ receptor are clinically useful. Desmopressin is a V₂receptor agonist that is approved in some territories for treatment ofdiabetes insipidus, primary nocturnal enuresis, nocturia, andcoagulation disorders including haemophilia A and von Willebrand'sdisease. Desmopressin binds and activates both the V₂ and V_(1b)receptors, with weaker activity on the V_(1a).

Desmopressin has been shown to be partly excreted via the kidneys (e.g.Fjellestad-Paulsen et al., 1993), and the half-life of desmopressin isincreased in patients with renal impairment (Ruzicka, et al. 2003;Agersoe et al. 2004). Agersoe et al. suggest that the increasedhalf-life might lead to prolonged antidiuretic effects and increase therisk of hyponatremia, a drop in serum sodium levels that can lead toadverse events such as seizures or coma. They further state that“although desmopressin appears to be safe and well-tolerated by patientswith impaired renal function, great caution should be exercised whentitrating towards an efficient dosing regimen, if patients withmoderately or severe renal function are to be treated with desmopressinat all.”

Therefore, there is a need for additional V₂ receptor agonists withreduced activity at the V_(1b) receptor. Additionally, V₂ receptoragonists that do not rely as heavily on the kidneys for elimination mayalso be desirable.

SUMMARY

In one embodiment, a compound is provided according to formula I or apharmaceutically acceptable salt thereof,

wherein R² is H, C₁-C₄ alkyl, halogen, —OH or —O—C₁-C₄ alkyl;R³ is H or —CH₂—OH or —C(O)—NR⁵R⁶;R⁴ is H or —C(═NH)—NH₂;R⁵ and R⁶ are independently H, C₁-C₆ alkyl, —CH₂-cyclopropyl,-cyclopropyl or arylalkyl with the proviso that R⁵ and R⁶ are not bothH;X and Y are independently —CH₂— or —S— with the proviso that if X is—CH₂—, Y is not —CH₂—;Z is —CHR⁷— or S and R⁷ is H or C₁-C₄ alkyl, halogen, —OH or —O—C₁-C₄alkyl;R⁸ is H or —CH₃; andAr is heteroaryl or phenyl optionally substituted with one C₁-C₄ alkyl,halogen, —OH or —O—C₁-C₄ alkyl.

In some embodiments, R⁵ and R⁶ are independently H, C₁-C₆ alkyl, orarylalkyl.

In some embodiments, R⁵ and R⁶ are independently H, C₁-C₆ alkyl orarylalkyl.

In some embodiments, R⁵ and R⁶ are not both H.

In some embodiments, only one of X and Y is —S—. In some embodiments, Xis —CH₂—. In some embodiments, X and Y are both —S—.

In some embodiments, Ar is thiophene.

In some embodiments, R⁸ is —CH₃.

In some embodiments, R³ is —C(O)—NR⁵R⁶. In certain of these embodiments,R⁵ is H and R⁶ is C₁-C₄ alkyl. In certain of these embodiments, both ofR⁵ and R⁶ is —CH₂CH₃.

In some embodiments, R² is a halogen. In certain of these embodiments,R² is —Cl. In certain of these embodiments, R² is —F.

Also provided herein, according to an embodiment, is a method oftreating one of diabetes insipidus, primary nocturnal enuresis, andnocturia comprising administering a therapeutically effective amount ofa compound according to formula I to a patient in need thereof. Theinvention also includes use of the compounds described herein intreating the conditions described herein, along with use of thecompounds described herein in the manufacture of a medicament fortreating the conditions described herein.

According to an embodiment, the compound of formula I is used in amedicament for the treatment of diabetes insipidus, primary nocturnalenuresis, or nocturia.

DETAILED DESCRIPTION

Unless otherwise stated, the following terms used in this application,including the specification and claims, have the definitions givenbelow. It must be noted that, as used in the specification and theappended claims, the singular forms “a,” “an” and “the” include pluralreferents unless the context clearly dictates otherwise. Definition ofstandard chemistry terms may be found in reference works, includingCarey and Sundberg (2007) Advanced Organic Chemistry 5^(th) Ed. Vols. Aand B, Plenum Press, New York. The practice of the present inventionwill employ, unless otherwise indicated, conventional methods ofsynthetic organic chemistry, mass spectroscopy, preparative andanalytical methods of chromatography, protein chemistry, biochemistryand pharmacology, within the skill of the art.

“Alkyl” is a C₁₋₁₂ straight, or branched chain alkyl. Branched alkylinclude iso-, sec-, and tert-configurations.

“Aryl” is mono- or bi-cyclic aromatic carbocyclic ring system of 5-12carbon atoms optionally substituted with C₁-C₄ alkyl, halogen, —OH or—O—C₁-C₄ alkyl. Exemplary mono- and bi-cyclic aromatic carbocyclic ringsystems include optionally substituted phenyl and optionally substitutednaphthyl.

“Arylalkyl” is an alkyl group which has as a substituent an aryl orheteroaryl group.

“Heteroaryl” is an aromatic heterocyclic five- or six-membered ringsystem optionally substituted with C₁-C₄ alkyl, halogen, —OH or —O—C₁-C₄alkyl. A five-membered heteroaromatic ring system is a monocyclicaromatic ring system having five ring atoms, wherein 1, 2, 3 or 4 ringatoms are independently selected from N, O and S. Exemplaryfive-membered heteroaromatic ring systems include optionally substitutedimidazolyl, thiazolyl, thienyl, furyl, pyrazolyl, and triazolyl. Asix-membered heteroaromatic ring system is a monocyclic aromatic ringsystem having six ring atoms, wherein 1, 2, 3 or 4 ring atoms areindependently selected from N, O and S. Exemplary six-memberedheteroaromatic ring systems include optionally substituted pyridyl,pyrimidyl and pyrazinyl.

One embodiment of the invention provides a pharmaceutical compositioncomprising compounds of the invention. In a first embodiment, thepharmaceutical composition further comprises one or morepharmaceutically acceptable excipients or vehicles, and optionally othertherapeutic and/or prophylactic ingredients. Such excipients are knownto those of skill in the art. The compounds of the present inventioninclude, without limitation, basic compounds such as free bases. Athorough discussion of pharmaceutically acceptable excipients and saltsis available in Remington's Pharmaceutical Sciences, 18th Edition(Easton, Pa.: Mack Publishing Company, 1990).

Examples of pharmaceutically acceptable salts include acid additionsalts, e.g. a salt formed by reaction with hydrohalogen acids such ashydrochloric acid and mineral acids, such as sulphuric acid, phosphoricacid and nitric acid, as well as aliphatic, alicyclic, aromatic orheterocyclic sulphonic or carboxylic acids such as formic acid, aceticacid, propionic acid, succinic acid, glycolic acid, lactic acid, malicacid, tartaric acid, citric acid, benzoic acid, ascorbic acid, maleicacid, hydroxymaleic acid, pyruvic acid, p-hydroxybenzoic acid, embonicacid, methanesulphonic acid, ethanesulphonic acid,hydroxyethanesulphonic acid, halobenzenesulphonic acid, trifluoroaceticacid, trifluoromethanesulphonic acid, toluenesulphonic acid andnaphthalenesulphonic acid. (see, e.g., Berge et al., J. Pharm. Sci. 66:119, 1977 and Wermuth, C. G. and P. H. Stahl, eds. Pharmaceutical Salts:Properties, Selection and Use. Zürich: Verlag Helvetica Chimica Acta,2002).

Depending on the intended mode of administration, the pharmaceuticalcompositions may be in the form of solid, semi-solid or liquid dosageforms, such as, for example, tablets, suppositories, pills, capsules,powders, liquids, suspensions, creams, ointments, lotions or the like,preferably in unit dosage form suitable for single administration of aprecise dosage. The compositions will include an effective amount of theselected drug in combination with a pharmaceutically acceptable carrierand, in addition, may include other pharmaceutical agents, adjuvants,diluents, buffers, etc.

The invention includes a pharmaceutical composition comprising acompound of the present invention including isomers, racemic ornon-racemic mixtures of isomers, or pharmaceutically acceptable salts orsolvates thereof together with one or more pharmaceutically acceptablecarriers and optionally other therapeutic and/or prophylacticingredients.

For solid compositions, conventional nontoxic solid carriers include,for example, pharmaceutical grades of mannitol, lactose, starch,magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose,magnesium carbonate and the like.

For oral administration, the composition will generally take the form ofa tablet, capsule, a softgel capsule nonaqueous solution, suspension orsyrup. Tablets and capsules are preferred oral administration forms. Insome embodiments, the tablet is a wafer, e.g., a fast-melt wafer. Insome embodiments, the wafer is administered via a sublingual route ofadministration. Tablets and capsules for oral use will generally includeone or more commonly used carriers such as lactose and corn starch.Lubricating agents, such as magnesium stearate, are also typicallyadded. When liquid suspensions are used, the active agent may becombined with emulsifying and suspending agents. If desired, flavoring,coloring and/or sweetening agents may be added as well. Other optionalcomponents for incorporation into an oral formulation herein include,but are not limited to, preservatives, suspending agents, thickeningagents and the like.

The dosages for therapy will depend on absorption, distribution,metabolism and excretion rates of the components of the combinationtherapy as well as other factors known to one of skill in the art.Dosage values will also vary with the severity of the condition to bealleviated. It is to be further understood that for any particularsubject, specific dosage regimens and schedules may be adjusted overtime according to the individual's need and the professional judgment ofthe person administering or supervising the administration of thetherapy. In some embodiments, an intravenous dose is around 100 ng. Insome embodiments, an oral dose is from 1 μg to 1 mg. In someembodiments, a nasal dose is from 3 mg to 6 mg.

Abbreviations used are:

Abbreviation Definition Ac Acetyl AcOH Acetic acid AVP

BTA N,O-Bis(trimethylsilyl)acetamide Bu butyl - alkyl residues may befurther denoted as n (normal, i.e. unbranched), i (iso), s (sec) and t(tertiary) Bzl Benzyl CH₃CN Acetonitrile DCE 1,2-dichloroethane DCMDichloromethane dDAVP

DIC N,N′-Diisopropylcarbodiimide DIPEA N,N-diisopropylethylamine DMFN,N-dimethylformamide dVP

Et Ethyl Fmoc 9-fluorenylmethoxycarbonyl HBTUO-Benzotriazole-N,N,N′,N′-tetramethyl- uronium,hexafluoro-phosphate HFIP1,1,1,3,3,3-hexafluoro-2-propanol HOBt N-hydroxybenzotriazole HPLC highperformance liquid chromatography iBu iso-butyl cPr cyclopropyl iPriso-propyl LC liquid chromatography Me methyl MeOH methanol MS massspectrometry NMM N-methylmorpholine Pbf2,2,4,6,7-pentamethyldihydrobenzofuran- 5-sulfonyl tBu tert-butyl tBuOHtert-butylalcohol TFA trifluoroacetic acid TIS triisopropylsilane TMOFTrimethyl orthoformate, trimethoxymethane Trt trityl [triphenylmethyl,(C₆H₅)₃C—]

Unless otherwise specified, L-amino acids were used and conventionalamino acid terminology is used. Examples of amino acids other than thetwenty conventional amino acids include:

Abbreviation Conventional Name Thi β-(2-thienyl)alanine Cpaβ-(4-chlorophenyl)alanine Fpa β-(4-fluorophenyl)alanine Hyp4-Hydroxyproline Thz 1,3-thiazolidine-4-carboxylic acid, thioproline Abu2-aminobutyric acid Agm Agmatine, (4-aminobutyl)guanidine Phe(4-Me)β-(4-methylphenyl)alanine Phe(4-Et) β-(4-ethylphenyl)alanineCompounds

The compounds of the invention have a structure of formula I:

and pharmaceutically acceptable salts thereof, wherein:R² is H, C₁-C₄ alkyl, halogen, —OH or —C₁-C₄ alkyl;R³ is H or —CH₂—OH or —C(O)—NR⁵R⁶;R⁴ is H or —C(═NH)—NH₂;R⁵ and R⁶ are independently H, C₁-C₆ alkyl, —CH₂-cyclopropyl,-cyclopropyl or arylalkyl with the proviso that R⁵ and R⁶ are not bothH;X and Y are independently —CH₂— or S with the proviso that if X is—CH₂—, Y is not —CH₂—;Z is —CHR⁷— or S and R⁷ is H or C₁-C₄ alkyl, halogen, —OH or —O—C₁-C₄alkyl;R⁸ is H or —CH₃;Ar is heteroaryl or phenyl optionally substituted with one C₁-C₄ alkyl,halogen, —OH or —O—C₁-C₄ alkyl.

TABLE 1 Example Compounds of the Invention. R³ Compound R²(configuration) R⁴ Ar X Y Z 1 Cl CH₂OH (R) C(═NH)—NH₂ 2-thienyl CH₂ SCH₂ 2 Me CH₂OH (R) C(═NH)—NH₂ 2-thienyl CH₂ S CH₂ 3 Cl C(═O)—NHEt (R)C(═NH)—NH₂ 2-thienyl CH₂ S CH₂ 4 Cl C(═O)—NHPr (R) C(═NH)—NH₂ 2-thienylCH₂ S CH₂ 5 Cl C(═O)—NHiBu (R) C(═NH)—NH₂ 2-thienyl CH₂ S CH₂ 6 OH CH₂OH(R) C(═NH)—NH₂ 2-thienyl CH₂ S CH₂ 7 Cl H C(═NH)—NH₂ 4- CH₂ S CH₂fluorophenyl 8 OH H C(═NH)—NH₂ 4- CH₂ S CH₂ fluorophenyl 9 OH H H2-thienyl CH₂ S CH₂ 10 Cl H C(═NH)—NH₂ 2-thienyl CH₂ S CH₂ 11 ClC(═O)—NHcPr (R) C(═NH)—NH₂ 2-thienyl CH₂ S CH₂ 12 Cl C(═O)—NH—CH₂-cPrC(═NH)—NH₂ 2-thienyl CH₂ S CH₂ (R) 13 Cl C(═O)—NHBzl (R) C(═NH)—NH₂2-thienyl CH₂ S CH₂ 14 Cl C(═O)—NHBu (R) C(═NH)—NH₂ 2-thienyl CH₂ S CH₂15 Cl C(═O)—NHiPr (R) C(═NH)—NH₂ 2-thienyl CH₂ S CH₂ 16 Cl C(═O)—NHiBu(R) C(═NH)—NH₂ 2-thienyl CH₂ S CH(OH) 17 Et CH₂OH (S) C(═NH)—NH₂2-thienyl CH₂ S CH₂ 18 Cl C(═O)—NHiBu (R) C(═NH)—NH₂ 2-thienyl S CH₂ CH₂19 Cl C(═O)—NHiBu (S) C(═NH)—NH₂ 2-thienyl CH₂ S CH₂ 20 Cl C(═O)—NHMe(R) C(═NH)—NH₂ 2-thienyl CH₂ S CH₂ 21 Cl C(═O)—NEt₂ (R) C(═NH)—NH₂2-thienyl CH₂ S CH₂ 22 Cl CH₂OH (S) C(═NH)—NH₂ 2-thienyl CH₂ S CH₂ 23 OHCH₂OH (S) C(═NH)—NH₂ 2-thienyl CH₂ S CH₂ 24 Cl CH₂OH (R) C(═NH)—NH₂ 4-CH₂ S CH₂ fluorophenyl 25 Cl CH₂OH (R) C(═NH)—NH₂ 2-thienyl S CH CH₂ 26Cl C(═O)—NHiBu (R) C(═NH)—NH₂ phenyl S CH CH₂ 27 Cl C(═O)—NHiBu (R)C(═NH)—NH₂ 2-thienyl S CH CH(OH) 28 Cl C(═O)—NHEt (R) C(═NH)—NH₂2-thienyl S S CH₂ 29 Cl C(═O)—NHEt (R) C(═NH)—NH₂ phenyl S S CH₂ 30 ClC(═O)—NHEt (R) C(═NH)—NH₂ 2-thienyl S CH CH₂ 31 Cl C(═O)—NHEt (R)C(═NH)—NH₂ 2-thienyl S CH CH(OH) 32 Cl C(═O)—NHEt (R) C(═NH)—NH₂ phenylCH₂ S CH(OH) 33 Cl C(═O)—NHEt (R) C(═NH)—NH₂ 2-thienyl CH₂ S S 34 ClC(═O)—NHEt (R) C(═NH)—NH₂ 2-thienyl S CH S 35 Cl C(═O)—NHPr (R)C(═NH)—NH₂ 2-thienyl CH₂ S S 36 Cl C(═O)—NH—CH₂-2- C(═NH)—NH₂ 2-thienylCH₂ S S thienyl (R) 37 Cl C(═O)—NH—CH₂-2- C(═NH)—NH₂ 4- CH₂ S S thienyl(R) fluorophenyl 38 OH C(═O)—NHBzl (R) C(═NH)—NH₂ 2-thienyl CH₂ S CH₂ 39Cl C(═O)—NHBzl (R) C(═NH)—NH₂ 2-thienyl CH₂ S S 40 Cl H C(═NH)—NH₂2-thienyl CH₂ S S 41 Cl H C(═NH)—NH₂ 4- CH₂ S S fluorophenylStructures of Compounds 1-41:

TABLE 2 Physicochemical properties of compounds 1-41 M + H M + H HPLCCompound (calculated) (observed) purity 1 976.4 976.4 99.3 2 956.5 956.498.3 3 1017.4 1017.4 100.0 4 1031.4 1031.5 100.0 5 1045.5 1045.5 100.0 6958.4 958.5 100.0 7 958.4 958.5 95.8 8 940.5 940.5 99.6 9 886.4 886.499.6 10 946.4 946.7 99.1 11 1029.4 1029.4 100.0 12 1043.4 1043.4 100.013 1079.4 1079.5 100.0 14 1045.5 1045.8 97.3 15 1031.4 1031.5 100.0 161061.5 1061.5 100.0 17 970.5 970.4 100.0 18 1045.5 1045.4 100.0 191045.5 1045.5 100.0 20 1003.5 1003.4 100.0 21 1045.5 1045.5 99.2 22976.4 976.5 98.2 23 948.4 958.5 96.6 24 988.4 988.5 99.3 25 976.4 976.5100.0 26 1039.5 1039.5 100.0 27 1061.5 1061.5 99.8 28 1035.4 1035.4 97.429 1029.4 1029.5 99.3 30 1017.4 107.5 99.5 31 1033.4 1033.5 99.2 321027.5 1027.5 99.2 33 1035.4 1035.5 100.0 34 1035.4 1035.5 100.0 351049.4 1049.7 99.3 36 1103.4 1103.7 100.0 37 1115.4 1115.7 99.2 381061.5 1061.7 98.3 39 1097.4 1097.7 96.8 40 964.3 964.6 99.6 41 976.4976.7 100.0

TABLE 3 In vitro assay data for compounds 1-41 EC50 % Efficacy EC50 %Efficacy Compound hV2-R hV2-R hV1b-R hV1b-R  1 0.10 102 140.91 42  20.39 104 806.52 27  3 0.29 92 171.74 62  4 0.33 92 249.07 49  5 0.22 100213.51 50  6 0.08 93 57.58 56  7 0.31 89 142.28 39  8 0.10 91 175.57 62 9 0.19 94 >10000 60 10 0.07 104 104.64 42 11 0.23 86 480.08 36 12 0.2190 321.63 43 13 0.19 100 149.75 37 14 0.26 98 187.54 36 15 0.45 81576.96 33 16 0.23 87 480.92 26 17 0.35 110 >10000 34 18 0.22 103 >1000029 19 0.29 98 >10000 19 20 0.27 106 351.12 37 21 0.25 102 535.72 21 220.14 96 382.84 44 23 0.10 92 518.47 53 24 0.35 102 223.19 45 25 0.08 11564.30 38 26 0.27 101 45.79 33 27 0.20 100 132.93 24 28 0.32 103 >1000020 29 0.38 103 >10000 16 30 0.19 114 123.00 33 31 0.10 92 258.02 25 320.29 98 150.43 21 33 0.10 103 159.76 32 34 0.11 93 40.21 34 35 0.21 111122.05 43 36 0.17 108 95.56 53 37 0.30 102 100.61 46 38 0.26 111 150.1248 39 0.31 111 328.73 72 40 0.12 106 140.67 50 41 0.22 108 114.44 42 42(dDAVP) 0.22 100 6.59 100 43 ([Val4]dDAVP) 0.05 89 24.13 98 44 (AVP)0.04 5.4

TABLE 4 Key to Amino Acid Nomenclature. Amino Claim Acid PositionNomenclature Cpa 2 R² = Cl Fpa 2 R² = F Phe(4-Me) 2 R² = —CH₃ Phe(4-Et)2 R² = —CH₂—CH₃ Thi 3

Fpa 3

Val 4 R⁸ = —CH₃ Abu 4 R⁸ = —H Hyp 7

Thz 7 Z = S Agm 8 R³ = H and R⁴ = —C(═NH)—NH₂

EXAMPLES

General Synthesis

Amino acid derivatives were purchased from commercial providers(Aapptec, EMD Millipore and Peptides International). Resins werepurchased from commercial suppliers (PCAS BioMatrix Inc. and EMDMillipore). All additional reagents, chemicals and solvents werepurchased from Sigma-Aldrich and VWR.

The compounds described herein were synthesized by standard methods insolid phase peptide chemistry utilising Fmoc methodology. The peptideswere assembled either manually, automatically using a Tribute PeptideSynthesizer (Protein Technologies Inc., Tucson, Ariz.) or by combinationof manual and automatic syntheses.

Preparative HPLC was performed on a Waters Prep LC System using aPrepPack cartridge Delta-Pack C18, 300 Å, 15 μm, 47×300 mm at a flowrate of 100 mL/min and/or on a Phenomenex Luna C18 column, 100 Å, 5 μm,30×100 mm at a flow rate of 40 mL/min. Analytical reverse phase HPLC wasperformed on an Agilent Technologies 1200rr Series liquid chromatographusing an Agilent Zorbax C18 column, 1.8 μm, 4.6×110 mm at a flow rate of1.5 mL/min. Final compound analyses were performed on an AgilentTechnologies 1200 Series chromatograph by reverse phase HPLC on aPhenomenex Gemini 110 Å C18 column, 3 μm, 2×150 mm at a flow rate of 0.3mL/min. Mass spectra were recorded on a MAT Finningan LCQ electrospraymass spectrometer. Unless stated otherwise, all reactions were performedat room temperature. The following standard reference literatureprovides further guidance on general experimental set up, as well as onthe availability of required starting material and reagents: Kates, S.A., Albericio, F., Eds., Solid Phase Synthesis: A Practical Guide,Marcel Dekker, New York, Basel, 2000; Greene, T. W., Wuts, P. G. M.,Protective Groups in Organic Synthesis, John Wiley Sons Inc., 2ndEdition, 1991; Stewart, J. M., Young, J. D., Solid Phase Synthesis,Pierce Chemical Company, 1984; Bisello, et al., J. Biol. Chem. 1998,273, 22498-22505; Merrifield, J. Am. Chem. Soc. 1963, 85, 2149-2154; andChang and White P. D., ‘Fmoc Solid Phase Peptide Synthesis: a PracticalApproach’, Oxford University Press, Oxford, 2000.

The following protecting groups were utilized to protect the given aminoacid side chain functional groups: Pbf(2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl) for Arg; tBu(t-butyl) for Tyr and Trt (trityl) for Cys, Gln and Asn.

Couplings of Fmoc-protected amino acids on the Tribute synthesizer weremediated with HBTU/NMM in DMF except for cysteine derivatives that werecoupled with DIC/HOBt in DMF. Single cycles of 30-60 minutes with a5-fold excess of activated Fmoc-protected amino acids were used duringthe synthesis. Removal of the Fmoc protecting group was monitored by UV.Multiple (up to 10 times, as needed) two-minute washes of the peptideresin with 20% piperidine in DMF were performed.

DIC/HOBt mediated couplings in DMF were employed for all amino acids inmanual mode. Single cycles of at least 2 hours with a 3-fold excess ofactivated Fmoc-protected amino acids were used during the synthesis. Thecompleteness of couplings was assessed with nihidrine (Kaiser) test.Removal of the Fmoc protecting group was achieved with a single 30 min.wash of the peptide resin with 20% piperidine in DMF.

Upon completion of the peptide synthesis, the peptide resins were washedwith DCM and dried in vacuo. The resins were treated with TFA/H₂O/TIS96:2:2 (v/v/v) for 2 h to remove the side-chain protecting groups withconcomitant cleavage of the peptide from the resin. The peptides werefiltered, precipitated with diethyl ether and decanted. To obtainpeptides with disulfide bridges, the precipitate was dissolved in neatTFA and the solution was subsequently poured into 10% acetonitrile inwater. In some cases an additional amount of acetonitrile was added tosolubilize the substrate. The linear peptide was oxidized with 0.1MI₂/MeOH. The oxidizer solution was added dropwise until yellow colorpersisted. The excess of iodine was reduced with solid ascorbic acid.The pH was then adjusted to about 4 with concentrated ammonia. Theobtained solution was loaded directly onto an HPLC prep column andeluted with a gradient of component B (see table below).

To cyclize peptides via amide bond formation the crude linear peptideswere dissolved in DMF and a solution of HBTU in DMF was also prepared.The peptide solution and the activator solution were addedinterchangeably to a volume of vigorously stirred DMF containing DIPEA.The pH was maintained at 9-10 with the addition of neat DIPEA. Thereaction was monitored by HPLC and typically no substrate peak wasdetected after the last portions of the activator and peptide solutionshave been added. The reaction mixture was diluted with 0.1% AcOH and theobtained solution was loaded directly onto an HPLC prep column andeluted with a gradient of component B.

Each crude peptide was purified with buffer system T. The fractions witha purity exceeding 93%, determined by reverse-phase analytical HPLC,were pooled and reloaded onto the column and eluted with buffer T toprovide trifluoroacetate salts. In some cases an additional purificationwith buffer system C was performed. To obtain acetate salts thefractions from runs with buffer T or C were reloaded onto the column andthe column was washed with 5 volumes of 0.1 M ammonium acetate. Thefinal product was eluted with buffer A. The fractions were pooled andlyophilized.

TABLE Buffer Compositions Buffer Component A Component B C 0.25 MTriethylammonium 60% acetonitrile, Perchlorate, pH 2.3 40% Component A T0.1% Trifluoroacetic acid (TFA) 60% acetonitrile, 0.1% TFA A   2% Aceticacid (AcOH) 60% acetonitrile, 2% AcOH

The compounds prepared were typically found to be at least about 95%pure.

Example 1—Compound 21

The 1-7 fragment was assembled manually starting from 7.8 g (6.9 mmol)of H-Pro-2-chlorotrityl AM resin (EMD Millipore, catalog number 856057,0.88 mmol/g). DIC/HOBt mediated couplings in DMF were employed. Singlecycles of at least 2 hours with a 3-fold excess of activatedFmoc-protected amino acids were used during the synthesis. Thecompleteness of couplings was assessed with ninhydrine test. Removal ofthe Fmoc protecting group was achieved with a single 30 min. wash of thepeptide resin with 20% piperidine in DMF. The following amino acidderivatives were used to assemble residues 1-7 of the resin-boundpeptide: Fmoc-Cys((CH₂)₃C(O)OtBu)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Val-OH,Fmoc-Thi-OH and Boc-Cpa-OH. After the 1-7 peptide fragment was assembledthe resin was washed thoroughly with DCM and treated with the DCM/HFIP7:3 (v/v) cocktail (2×1 h, 30 mL each). The solvents were thenevaporated and the residue was precipitated with ethyl ether, filteredand dried in vacuo. 5.79 g (4.63 mmol, 67%) of the crude protectedlinear peptide was obtained. (The remainder of this product was used inthe synthesis of other compounds as described herein.)

H-D-Arg-NEt₂×2TFA.

2.81 g (5.4 mmol) of Boc-D-Arg(Pbf)-OH (Chem Impex, cat #05282), 1.95 mL(11.2 mmol) of DIPEA and 2.13 g (5.6 mmol) of HBTU were dissolved in 10mL DMF. 0.62 mL (6 mmol) of diethylamine was subsequently added to thesolution. No substrate was detected by analytical HPLC after 5 min. Thereaction mixture was poured into 500 mL of water and the precipitate wasseparated by centrifugation and dried in vacuo. The residue was treatedwith 20 mL TFA/TIS/H₂O (96/2/2, v/v/v) for 1 h and the solvents wereevaporated. The residue was treated with ethyl ether and decanted. 1.65g (3.6 mmol, 67%) of semisolid derivative was obtained which was used inthe subsequent step without purification.

Coupling with H-D-Arg-NEt₂.

2.3 g (c.a. 1.86 mmol) of the linear protected peptide and 0.76 g (2mmol) of HBTU were dissolved in 10 mL DMF containing 0.73 mL (4.2 mmol)DIPEA. 0.93 g (2.05 mmol) of H-D-Arg(Pbf)-OH×2TFA in 1 mL DMF wassubsequently added to the reaction mixture. No substrate was detectedafter 5 min by HPLC. The product was precipitated with 1 L of water,filtered off and dried in vacuo. 2.6 g (1.78 mmol, 96%) of crudeprotected linear peptide was obtained. The fully protected peptide wastreated with 20 mL TFA/TIS/H₂O (96/2/2, v/v/v) for 1 h and the solventwas evaporated. The unprotected linear peptide was precipitated withethyl ether and lyophilized. Yield 1.82 g (1.55 mmol, 83%).

The entire amount of the linear peptide was dissolved in 50 mL of DMF. Asolution of 0.59 g (c.a. 1.55 mmol) HBTU in 10 mL of DMF was alsoprepared. The peptide solution and the activator solution were addedinterchangeably to 50 mL of vigorously stirred DMF containing 200 μL ofDIPEA in 10 portions of 5 mL and 1 mL, respectively. The pH wasmaintained at 9-10 with the addition of neat DIPEA. No substrate peakwas detected by HPLC after the last portions of the activator andpeptide solutions have been added. The reaction mixture was diluted with0.1% AcOH to 1 L. The obtained solution was loaded directly onto an HPLCprep column and purified with buffer system T eluted with a gradient ofcomponent B (see table above). The fractions with a purity exceeding93%, determined by reverse-phase analytical HPLC, were pooled andreloaded onto the column. The column was washed with 5 volumes of 0.1MAcONH₄ and the compound was subsequently eluted with buffer C to provideacetate salt. The fractions were pooled and lyophilized. 703.1 mg (0.60mmol, 22% overall based on 89.6% peptide content) of white peptidepowder was obtained. The product purity was determined by analyticalHPLC as 99.7% and the observed M+H was 1045.6 (calc. M+H=1045.5).

Example 2—Compound 10

2.32 g (about 1.8 mmol) of the protected linear peptide prepared in thesynthesis of SEQ ID NO: 21 was dissolved in 7 mL of DMF and 0.63 mL (3.6mmol, 2 eq) NMM was added followed by 0.76 g (2 mmol, 1.1 eq) HBTU. In aseparate vial, 0.64 g (2.8 mmol, 1.5 eq) of agmatine sulfate wassuspended in 7 mL DMF containing 0.49 mL (2.8 mmol) of DIPEA.N,O-Bis(trimethylsilyl)acetamide (BTA, Sigma-Aldrich, cat #128910) wasadded to the occasionally vortexed/sonicated suspension. A clearsolution was obtained after 4 eq of BTA were added to the suspension.The two solutions were combined and no substrate peptide was detected byHPLC after 5 min. The product was precipitated with 1 L of water,filtered off and dried in vacuo. The resulting powder was treated with50 mL of the TFA/TIS/H₂O 96/2/2 (v/v/v) cocktail for 1.5 hrs. Thesolvent was evaporated and the linear peptide was precipitated withethyl ether, reconstituted in water/acetonitrile and lyophilized.

The entire amount of peptide (2.13 g, c.a. 2 mmol) obtained in thepreceding step was dissolved in 50 mL of DMF. A solution of 0.76 g (2mmol) HBTU in 10 mL of DMF was also prepared. The peptide solution andthe activator solution were added interchangeably to 50 mL of vigorouslystirred DMF containing 400 μL of DIPEA in 10 portions of 2.5 mL and 0.5mL, respectively. The pH was maintained at 9-10 with the addition ofneat DIPEA. No substrate peak was detected after the last portions ofthe activator and peptide solutions have been added. The reactionmixture was diluted with 0.1% AcOH to 1 L and the obtained solution wasloaded directly onto an HPLC prep column and purified with buffer systemT eluted with a gradient of component B (see table above). The fractionswith a purity exceeding 93%, determined by reverse-phase analyticalHPLC, were pooled and reloaded onto the column. The column was washedwith 5 volumes of 0.1M AcONH₄ and the compound was subsequently elutedwith buffer C to provide acetate salt. The fractions were pooled andlyophilized. 656.7 mg (0.62 mmol, 23% overall yield based on 89.5%peptide content) of white peptide powder was obtained. The productpurity was determined by analytical HPLC as 100.0% and the observed M+Hwas 946.6 (calc. M+H was 946.4).

Example 3—Compound 5

1 g (c.a. 1 mmol) of FMPB AM resin (EMD Millipore, cat #855028) wasswollen in 15 ml of DCE/TMOF 1:1 mixture. To the resin suspensionisobutyl amine (1.5 mL, 15 mmol) was added followed by 3.2 g solidsodium triacetoxyborohydride. The suspension was shaken overnight. Theresin was washed with MeOH, DMF and DCM and was subsequently acylatedwith Fmoc-D-Arg(Pbf)-OH/DIC (4 eq) in DCM. The resin was washed with DMFand tested for acylation completeness with the chloranil test(negative). The resin was split into three equal portions and thesynthesis was continued at 0.33 mmol scale on the Tribute Synthesizer.Single couplings mediated with HBTU/NMM in DMF or with DIC/HOBt (forCys) with a 5-fold excess of Fmoc-protected amino acids were used. TheFmoc protecting group was removed with several consecutive 2 min. washeswith 20% piperidine in DMF. The following amino acid derivatives wereused in the automatic synthesis: Fmoc-Pro-OH,Fmoc-Cys((CH₂)₃C(O)OtBu)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Val-OH, Fmoc-Thi-OHand Boc-Cpa-OH. After the entire peptide sequence has been assembled thepeptide was cleaved from the resin with 20 mL of TFA/H₂O/TIS 96:2:2(v/v/v) for 2 h. The linear peptide was dissolved in 40 mL of DMFcontaining 200 μL of DIPEA. A solution of 152 mg (c.a. 0.4 mmol) HBTU in5 mL of DMF was also prepared. The peptide solution and the activatorsolution were added interchangeably to 40 mL of vigorously stirred DMFin 10 portions of 4 mL and 0.5 mL, respectively. The pH was maintainedat 9-10 with the addition of neat DIPEA. No substrate peak was detectedby HPLC after the last portion of the activator solution has been added.The reaction mixture was diluted with 0.1% AcOH to 1 L. The obtainedsolution was loaded directly onto an HPLC prep column. The compound waspurified by three consecutive runs in buffer T.

The fractions exceeding 97% purity were pooled and lyophilized. 49.0 mg(0.042 mmol, 12% overall, assuming 90% peptide content) of white peptidepowder was obtained. The product purity was determined by analyticalHPLC as 99.5% and the observed M+H was 1045.6 (calc. M+H=1045.5).

Example 4—Compound 9

0.37 g (c.a. 0.3 mmol) of 1,4-diaminobutane-2-chlorotrityl resin (EMDMillipore, cat #856085) was swollen in 10 mL of DMF and the resin placedin an automatic synthesis reaction vessel. The peptide assembly wascarried out on the Tribute Synthesizer. Single couplings mediated withHBTU/NMM in DMF or with DIC/HOBt (for Cys) with a 5-fold excess ofFmoc-protected amino acids were used. The Fmoc protecting group wasremoved with several consecutive 2 min. washes with 20% piperidine inDMF. The following amino acid derivatives were used in the automaticsynthesis: Fmoc-Pro-OH, Fmoc-Cys((CH₂)₃C(O)OtBu)-OH, Fmoc-Asn(Trt)-OH,Fmoc-Val-OH, Fmoc-Thi-OH and Boc-Tyr(tBu)-OH. After the entire peptidesequence has been assembled the peptide was cleaved from the resin with30 mL of HFIP/DCM 3:7 (v/v) for 2 h. The resin was filtered and thesolvents were evaporated. The linear protected peptide was precipitatedwith anhydrous ethyl ether. The precipitate was decanted and suspendedin 20 mL acetonitrile. 111 mg (0.4 mmol) of Z(2-Cl)-OSu and 0.136 mL(0.8 mmol) DIPEA were subsequently added to the suspension. After thesubstrate has dissolved, the solvent was evaporated and the residue wastreated with 20 mL of the TFA/TIS/H₂O 95/2.5/2.5 cocktail for 1.5 h. TFAwas then evaporated and the residue was precipitated with diethyl ether.The crude linear peptide was dissolved in 100 mL of DMF containing 200μL of DIPEA. A solution of 120 mg (0.31 mmol) HBTU in 5 mL of DMF wassubsequently added to the vigorously stirred reaction mixture. After 30min. the reaction mixture was diluted with 1 L 0.1% AcOH and theobtained solution was uploaded onto prep HPLC column. The cyclic peptidewas eluted with fast (c.a. 3% MeCN/min.) in buffer system T. Fractionsexceeding 97% purity by analytical HPLC were pooled and lyophilized. Theliophilizate was treated with 5 mL of the TMSBr/thioanisole/TFA cocktail(1/1/6, v/v/v) for 1 h at 0° C. TFA was evaporated and the peptide wasprecipitated with ethyl ether. The final product was purified by asingle run in buffer T.

The fractions exceeding 97% purity were pooled and lyophilized. 77.5 mg(0.079 mmol, 26% overall, assuming 90% peptide content) of white peptidepowder was obtained. The product purity was determined by analyticalHPLC as 99.6% and the observed M+H was 886.4 (calc. M+H=886.4).

Example 5—Compound 17

0.43 g (c.a. 0.3 mmol) of H-Arg(Pbf)-O-2-chlorotrityl resin (EMDMillipore, cat #856067) was swollen in 10 mL of DMF and the resin placedin an automatic synthesis reaction vessel. The peptide assembly wascarried out on the Tribute Synthesizer. Single couplings mediated withHBTU/NMM in DMF or with DIC/HOBt (for Cys) with a 5-fold excess ofFmoc-protected amino acids were used. The Fmoc protecting group wasremoved with several consecutive 2 min. washes with 20% piperidine inDMF. The following amino acid derivatives were used in the automaticsynthesis: Fmoc-Pro-OH, Fmoc-Cys((CH₂)₃C(O)OtBu)-OH, Fmoc-Asn(Trt)-OH,Fmoc-Val-OH and Fmoc-Thi-OH. After the 3-8 peptide sequence has beenassembled Fmoc-Phe(4-Et)-OH was coupled manually using DIC/HOBt methodwith 2-fold excess of reagents. The Fmoc group was then replaced withthe Boc group by treating the resin with 20% PIP/DMF for 30 min. andacylating the N-terminal amino function with Boc₂O in DMF. The linearpeptide was cleaved from the resin with 30 mL of HFIP/DCM 3:7 (v/v) for2 h. The resin was filtered and the solvents were evaporated. The linearprotected peptide was precipitated with anhydrous ethyl ether. Theprecipitate was decanted and dried in vacuo. 450 mg of the crudeprotected peptide was obtained. The entire amount of the peptide (c.a.0.3 mmol) was dissolved in 10 mL 1,2-dichloroethane containing 0.5 mLDMF and 61 μL (0.45 mmol) NMM. The solution was cooled to 0° C. on icebath and 61 μL (0.45 mmol) of isobutyl chloroformate was added. Thereaction mixture was magnetically stirred for 10 min. at 0° C. Asolution of 160 mg (4.5 mmol) sodium borohydride in 5 mL water was addedin one portion. The reaction was diluted with 200 mL water and theproduct was separated by centrifugation and dried in vacuo. The productwas then was treated with 20 mL of the TFA/TIS/H₂O 95/2.5/2.5 cocktailfor 1.5 h. TFA was then evaporated and the residue was precipitated withdiethyl ether. The crude linear peptide was dissolved in 80 mL of DMFcontaining 200 μL of DIPEA. A solution of 61 mg (0.15 mmol) HBTU in 5 mLof DMF was subsequently added to the vigorously stirred reactionmixture. After 30 min. the reaction mixture was diluted with 1 L 0.1%AcOH and the obtained solution was uploaded onto prep HPLC column. Thecyclic peptide was purified by two consecutive runs in buffer T.

The fractions exceeding 97% purity were pooled and lyophilized. 41.7 mg(0.039 mmol, 13% overall, assuming 90% peptide content) of white peptidepowder was obtained. The product purity was determined by analyticalHPLC as 95.1% and the observed M+H was 970.6 (calc. M+H=970.5).

Experimental (Biological Testing)

In Vitro Receptor Assays

V₂ Receptor Activity

Agonist activity of compounds on the human V₂ receptor (h V₂R) wasdetermined in a transcriptional reporter gene assay by transientlytransfecting an h V₂ receptor expression DNA into HEK-293 (humanembryonic kidney 293 cell line) cells in concert with a reporter DNAcontaining intracellular calcium responsive promoter elements regulatingexpression of firefly luciferase. See Boss, V., Talpade, D. J., Murphy,T. J. J. Biol. Chem. 1996, May 3; 271(18), 10429-10432 for furtherguidance on this assay. Cells were exposed to serial dilutions ofcompounds diluted 10-fold per dose for 5 h, followed by lysis of cells,determination of luciferase activity, and determination of compoundefficacies and EC₅₀ values through non-linear regression. Desmopressin(dDAVP) was used as an internal control in each experiment. Results forthe tested compounds are shown in Table 3

V_(1b) Receptor Activity

To determine selectivity, compounds were tested in luciferase-basedtranscriptional reporter gene assays expressing the human V_(1b)receptor (hV_(1b)R). Agonist activity of compounds on the hV_(1b)R wasdetermined in a transcriptional reporter gene assay in a Flp-In™ 293cell line (HEK-flpin) stably transfected to express the hV_(1b)R. Thesecells are transiently transfected with an NFAT responsiveelements-luciferase (NFAT-Luc) reporter. Cells were exposed to serialdilutions of compounds diluted 10-fold per dose for 5 hours, followed bylysis of cells, determination of luciferase activity, and determinationof compound efficacies and EC₅₀ values through non-linear regression.AVP was used as an internal control in each experiment. Results for thetested compounds are shown in Table 3.

Renal Clearance

Desmopressin is cleared from the body primarily by the kidneys (“renalclearance”). Compounds of the invention have a higher extent ofclearance through non-renal mechanisms. Pharmacokinetic experiments wereperformed in nephrectomized and sham-operated rats. Non-renal clearance(CLnr) was determined in nephrectomized rats, and total clearance wasdetermined in sham-operated rats (CLsham). % Non-Renal Clearance wascalculated by (CLnr/CLsham)×100.

For the pharmacokinetic studies, adult male Sprague Dawley rats werecatheterized via the jugular vein (for compound administration) andcarotid artery (for blood collection). A solution containing multiplecompounds (cassette dosing) was injected into the jugular vein catheter(0.1 mg FB/ml of each compound, 0.3 ml/animal; nominal dose of 0.1 mgFB/kg/compound). Blood samples were collected at 2, 6, 10, 15, 20, 30,45, 60, 90, and 120 minutes post-administration using an automated bloodsampling system, the Instech Laboratories Automated Blood Sampling Unit2nd generation (ABS2). Plasma was prepared from whole blood using K2EDTAas anticoagulant. Subsequent bioanalysis of samples included compoundextraction and plasma concentration determination using standard LC/MSmethods. Analyte concentration was calculated from peak areas andcalibration curves. PK parameters were obtained by best fitting of thecompound concentration-time profile for each animal by means of anoncompartmental analysis method using WINNONLIN™ v6.3 software(Pharsight Corporation).

Antidiuresis

Compounds were tested for antidiuretic activity in a rat model. Inbrief, catheterized euvolemic Sprague Dawley rats were placed inmetabolic cages. Each metabolic cage was set up for continuousmeasurement of spontaneous urine output via force transducers placedabove the urine collection vials to monitor and record the time courseof urine output using NOTOCORD™ software. The rats received anintravenous infusion of test compound or vehicle for three hours using asyringe pump and swivel/tether method. Data for urine output wascollected during the administration of compound (0-3 hours) and wascollected for the 5 hours post-administration. In some cases, urineosmolality was also determined. Compounds of the invention showedantidiuretic activity.

Pharmaceutical Compositions

There is also provided the use of a compound of formula (I), as definedherein, as a pharmaceutical. Further provided a pharmaceuticalcomposition comprising a compound of formula (I), as defined herein, asactive ingredient in association with a pharmaceutically acceptableadjuvant, diluent or carrier.

The pharmaceutical composition may be adapted for various modes ofadministration including for example, oral and nasal. The compositionmay thus for instance be in the form of tablets, capsules, powders,microparticles, granules, syrups, suspensions and solutions.

The pharmaceutical composition may optionally comprise e.g. at least onefurther additive selected from a disintegrating agent, binder,lubricant, flavouring agent, preservative, colourant and any mixturethereof. Examples of such and other additives are found in ‘Handbook ofPharmaceutical Excipients’; Ed. A. H. Kibbe, 3^(rd) Ed., AmericanPharmaceutical Association, USA and Pharmaceutical Press UK, 2000.

Methods of Treatment

In a further aspect the present invention provides the use of a compoundas outlined above for the manufacture of a medicament for treatment ofdiabetes insipidus, primary nocturnal enuresis, and nocturia. Further,methods of treating diabetes insipidus, primary nocturnal enuresis, andnocturia are provided. As used herein ‘treatment’ means the alleviationof symptoms, postponement of the onset of the disease and/or the cure ofthe disease when a compound of the invention is administered in asuitable dose.

The typical dosage of the compounds according to the present inventionvaries within a wide range and will depend on various factors such asthe individual needs of each patient and the route of administration.The dosage may be administered once daily or more frequently than oncedaily, e.g. intermittently. A physician of ordinary skill in the artwill be able to optimize the dosage to the situation at hand.

All publications and patent applications cited in this specification areherein incorporated by reference as if each individual publication orpatent application were specifically and individually indicated to beincorporated by reference.

Although the foregoing invention has been described in some detail byway of illustration and example for purposes of clarity ofunderstanding, it will be readily apparent to one of ordinary skill inthe art in light of the teachings of this invention that certain changesand modifications may be made thereto without departing from the spiritor scope of the appended claims.

The invention claimed is:
 1. A vasopressin-2 receptor agonist of formulaI:

or a pharmaceutically acceptable salt thereof, wherein: R² is halogen;R³ is —C(O)—NR⁵R⁶; R⁴ is C(═NH)—NH₂; R⁵ and R⁶ are independently H,isobutyl, —CH2-phenyl, butyl, or ethyl, with the proviso that R⁵ and R⁶are not both H; X is —CH₂—; Y is —S—; Z is —CHR⁷— or —S—, wherein R⁷ isH; R⁸ is —CH₃; and Ar is thiophene.
 2. The vasopressin-2 receptoragonist of claim 1, wherein both of R⁵ and R⁶ are —CH₂CH₃.
 3. Thevasopressin-2 receptor agonist of claim 1, wherein R² is —Cl.
 4. Thevasopressin-2 receptor agonist of claim 1, wherein R² is —F.
 5. Apharmaceutical composition comprising a vasopressin-2 receptor agonistaccording to claim 1 and a pharmaceutically acceptable carrier.
 6. Thevasopressin-2 receptor agonist of claim 1, selected from compound 5:


7. The vasopressin-2 receptor agonist of claim 1, wherein the agonistexhibits reduced activity at the V_(1b) receptor as compared todesmopressin.
 8. A method of treating diabetes insipidus, primarynocturnal enuresis, or nocturia, comprising administering atherapeutically effective amount of a vasopressin-2 receptor agonist ofclaim 1 to a patient in need thereof.